The present invention relates to 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivatives, to pharmaceutical compositions comprising the same and to the use of these 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivatives in therapy, especially in the treatment of pain.
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain can be nociceptive or neuropathic in origin. Pain experienced as a consequence of arthritis is generally nociceptive in nature, caused by inflammation of tissue and stimulation of nociceptors. Major indications driving prevalence of nociceptive pains are low back pain, osteoarthritis, post-operative pain, and cancer-related pain. Major unmet needs for nociceptive pain are for improved efficacy and fewer side effects. The chronic pain market is currently dominated by non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase COX-2 inhibitors. NSAIDs provide adequate analgesia to relieve mild to moderate pain and usually have greater effectiveness in inflammatory pain. Individual NSAIDs vary in their efficacy, and these variations are partly determined by differing COX-1/COX-2 selectivities. Consequently, patients may require to be treated with several different drugs before their pain is adequately treated. Side effects associated with drug therapy are an important factor in treatment choice, especially as many pain syndromes are long-term chronic conditions.
The most common side effects of NSAIDs are constipation and indigestion; most anti-inflammatory drugs are acidic in nature and promote acid production in the stomach. Other, serious side effects are gastrointestinal complications such as gastric ulcers, mucosal damage and peptic erosion. NSAIDs are thought to account for as many as 107,000 hospitalizations and 16,500 deaths due to ulcer complications in the US each year (Singh, Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Am. J. Med., 1998, 105: 31S-38S). Whilst COX-2 inhibitors have an improved gastrointestinal side effect profile, their use has been associated with increased risk of myocardial infarction and stroke and increased risk of hypertension.
Neuropathic pain, defined as chronic pain caused by injury, disease or dysfunction of the nervous system, is present in ˜1% of the population; the largest patient populations include those with painful diabetic peripheral neuropathy, and those with neuralgia that persists after an attack of herpes zoster (post-herpetic neuralgia). It is characterized by a complex combination of symptoms, including spontaneous pain that can occur in the absence of tissue damage. Patients suffering from neuropathic pain also have increased sensitivity both to stimuli normally perceived as painful (hyperalgesia), as well as to stimuli that do not normally provoke pain (allodynia). These symptoms are often refractory to conventional analgesic therapies, with most patients achieving incomplete relief of their symptoms. Currently, antidepressants, anticonvulsants and opioids remain first-line treatment, with gabapentin as the gold standard. All of these drugs have significant side-effects that are dose limiting. In addition, efficacy is a considerable problem in the neuropathic pain market with current treatments showing a maximum of 50% reduction in overall pain scores from baseline. Consequently, there remains an unmet medical need for agents that have higher efficacy/responder rate, and with reduced side-effects compared with currently used drugs.
Emerging clinical evidence, as well as anecdotal reports from patients self-medicating with cannabis, suggest that cannabinoid receptor agonists may have a role in treating pain (Fox A, Bevan S., Therapeutic potential of cannabinoid receptor agonists as analgesic agents. Expert Opin Investig Drugs, 2005, 14, 695-703). G W Sativex, a 1:1 ratio of Δ9-THC and cannabidiol in an oromucosal spray formulation that allows individualised dosing for the treatment of neuropathic pain has been launched by GW Pharmaceuticals. Clinical studies with Sativex have demonstrated efficacy in patients with intractable pain (chronic neuropathic pain, pain due to brachial plexus nerve injury, allodynic peripheral neuropathic pain and advanced cancer pain), rheumatoid arthritis and symptoms associated with multiple sclerosis (pain, spasticity, poor bladder control and disrupted sleep; (Barnes M P. 2006. Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain. Expert Opin. Pharmacother. 7(5): 607-615).
Two types of cannabinoid receptors have been identified. The cannabinoid CB1 receptor is located primarily in the central nervous system (CNS; brain and spinal cord), but is also expressed by peripheral neurones and to a lower extent in other peripheral tissues. The cannabinoid CB2 receptor is mainly confined to the periphery, mostly in immune cells (Howlett, A. C. et al, International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors. Pharmacol. Rev. 54, 161-202, 2002). While the conventional CB1 receptor agonists and CB1/CB2 receptor agonists, such as tetrahydrocannabinol (THC) are highly effective in models of pain in animals, their therapeutic utility in man is limited by undesired CNS side-effects, such as psychoactive effects, and by abuse potential (Chapman, V. and Finn, D. P. “Analgesic effects of cannabinoids: sites and mechanism of action.” Rev. Analg. 7, 25-39, 2003).
Recent literature evidence suggests that selective activation of the CB2 receptor may constitute a novel strategy for treating pain and inflammation without undesirable CNS side effects. (Guindon, J. and Hohmann, A., “Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain”, Br. J. Pharmacol., 2008, 153, 319-334). Activation of the CB2 receptor was found to inhibit acute, inflammatory and neuropathic pain responses in animal models (Whiteside G. T., Lee G. P., Valenzano K. J. “The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists, Current Med. Chem., 2007, 14, 917-936). CB2 knock-out mice studies also support a role for CB2 receptors in pain (Malan T P, Jr, Ibrahim M M, Lai J, Vanderah T W, Makriyannis A and Porreca F. CB2 cannabinoid receptor agonists: pain relief without psychoactive effects? Curr. Opin. Pharmacol. 2003; 3: 62-67).
The cellular mechanisms contributing to CB2-mediated antinociception are not yet clear, but it has been proposed that activation of CB2 receptors affects inflammatory pain indirectly via modulation of immune cell activity, resulting in decreased release of mediators at the local site of inflammation. In addition to a peripheral effect, recent publications suggest that CB2 receptor agonists can also interact with CB2 receptors expressed on peripheral neurons and activated microglia to modulate pain transmission (Beltramo et al., 2006. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci. 23(6):1530-80; Romero-Sandoval & Eisenach, 2007. Spinal cannabinoid receptor type 2 activation reduces hypersensitivity and spinal cord glial activation after paw incision. Anesthesiology 106(4):787-94).
In summary, CB2 receptor agonists may be suitable for the treatment of acute and chronic pain conditions, such as osteoarthritis, rheumatoid arthritis and acute post-operative pain and neuropathic pain. The absence of catalepsy with CB2 agonists in preclinical models shows promise for the treatment of acute and chronic pain without undesired CNS side effects.
N-(Biphenyl-4-ylmethyl)piperidine, -morpholine and -piperazine derivatives have recently been disclosed in the International Patent Application WO 2007/070760 (Boehringer Ingelheim International) as CB2 modulators useful in the treatment of inflammatory diseases, autoimmune diseases and pain.
There remains a need for further selective CB2 cannabinoid receptor agonists as therapeutic agents in the treatment of pain.